CN115894329A - Synthesis method of axial chiral indole derivative containing 2-thiocyano-3-aryl - Google Patents
Synthesis method of axial chiral indole derivative containing 2-thiocyano-3-aryl Download PDFInfo
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- CN115894329A CN115894329A CN202211630820.XA CN202211630820A CN115894329A CN 115894329 A CN115894329 A CN 115894329A CN 202211630820 A CN202211630820 A CN 202211630820A CN 115894329 A CN115894329 A CN 115894329A
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- 150000002475 indoles Chemical class 0.000 title claims abstract description 124
- 238000001308 synthesis method Methods 0.000 title abstract description 4
- 239000000758 substrate Substances 0.000 claims abstract description 84
- ZPIHHIRJUPXETJ-UHFFFAOYSA-N 2-iodo-1h-indole Chemical compound C1=CC=C2NC(I)=CC2=C1 ZPIHHIRJUPXETJ-UHFFFAOYSA-N 0.000 claims abstract description 59
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 24
- 125000005619 boric acid group Chemical group 0.000 claims abstract description 22
- 230000003197 catalytic effect Effects 0.000 claims abstract description 17
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical group COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000002156 mixing Methods 0.000 claims abstract description 14
- WUFYFIRKVXAESN-UHFFFAOYSA-N methyl 3-iodo-1h-indole-6-carboxylate Chemical compound COC(=O)C1=CC=C2C(I)=CNC2=C1 WUFYFIRKVXAESN-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000009471 action Effects 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims description 47
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 42
- 239000012046 mixed solvent Substances 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 125000005031 thiocyano group Chemical group S(C#N)* 0.000 claims description 22
- -1 thiocyano indole derivative Chemical class 0.000 claims description 19
- 239000003153 chemical reaction reagent Substances 0.000 claims description 17
- 239000008367 deionised water Substances 0.000 claims description 16
- 229910021641 deionized water Inorganic materials 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 7
- 239000004327 boric acid Substances 0.000 claims description 7
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- RLROEHOSBRRSIW-UHFFFAOYSA-N disodium;iron(3+) Chemical compound [Na+].[Na+].[Fe+3] RLROEHOSBRRSIW-UHFFFAOYSA-N 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 26
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 abstract description 12
- 150000004820 halides Chemical class 0.000 abstract description 7
- 229910052717 sulfur Inorganic materials 0.000 abstract description 6
- 239000011593 sulfur Substances 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000010791 quenching Methods 0.000 description 34
- 230000000171 quenching effect Effects 0.000 description 32
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
- 239000003795 chemical substances by application Substances 0.000 description 28
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000007789 gas Substances 0.000 description 22
- 230000001681 protective effect Effects 0.000 description 22
- 238000000746 purification Methods 0.000 description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- 239000000543 intermediate Substances 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 19
- 238000003818 flash chromatography Methods 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- 235000017557 sodium bicarbonate Nutrition 0.000 description 15
- 229910052786 argon Inorganic materials 0.000 description 12
- 239000012298 atmosphere Substances 0.000 description 11
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 8
- 239000012467 final product Substances 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- LINDOXZENKYESA-UHFFFAOYSA-N TMG Natural products CNC(N)=NC LINDOXZENKYESA-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000004896 high resolution mass spectrometry Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- XBNOMKROXZGMFW-UHFFFAOYSA-N 3-[(3-hydroxyphenyl)disulfanyl]phenol Chemical compound OC1=CC=CC(SSC=2C=C(O)C=CC=2)=C1 XBNOMKROXZGMFW-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- ASMQGLCHMVWBQR-UHFFFAOYSA-M diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)([O-])OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-M 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- 125000001743 benzylic group Chemical group 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- BYIUTLKZMLKUED-UHFFFAOYSA-N CC(C)(C(C)(CSC#N)O)O Chemical compound CC(C)(C(C)(CSC#N)O)O BYIUTLKZMLKUED-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical class [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- LLQDBKQZOHSGFL-UHFFFAOYSA-N S(C#N)N1C(C=2C(C1=O)=CC=CC=2)=O Chemical compound S(C#N)N1C(C=2C(C1=O)=CC=CC=2)=O LLQDBKQZOHSGFL-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000005620 boronic acid group Chemical group 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000007805 chemical reaction reactant Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- YMWUJEATGCHHMB-DICFDUPASA-N deuterated dichloromethane Substances [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000001741 organic sulfur group Chemical group 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000006365 thiocyanation reaction Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a synthesis method of an axial chiral sulfur cyano-containing indole derivative, belongs to the technical field of indole derivative synthesis, and particularly relates to a method for generating an indole derivative A or a salt thereof by reacting a substrate containing a boric acid group with an iodoindole substrate under the action of a catalytic system; or, mixing indole derivative A or its salt with BBr 3 After the reaction, the indole derivative B or the salt thereof is generated by the reaction with halide; the catalytic system used in the invention at least comprises tetraaminopalladium dichloride, and also comprises N, N ' - (1,2-ethanediyl) ferric (III) bisaspartate or 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl, and the iodoindole substrate used is 3-iodo-1H-indole-6-carboxylic acid methyl ester, so that the method has high yield.
Description
Technical Field
The invention belongs to the technical field of indole derivative synthesis, and particularly relates to a synthesis method of an axial chiral 2-thiocyano-3-aryl-containing indole derivative.
Background
The organic sulfur-containing compound containing the thiocyano group has great interest for chemists due to the unique pharmacological activity and synthesis application value, has the figure in molecular skeletons of a plurality of natural products and medicaments, and can be used for discovering that the thiocyano group carried by the organic compound has unsaturation in chemical meaning and can generate a plurality of effective functional group conversions by analyzing the structure of the thiocyano group organic compound.
Electrophilic thiocyanation of unsaturated bonds is one of the important strategies for the direct and efficient construction of thiocyano-containing compounds, and has received considerable attention in recent years. In 2019, chen Zhimin topic group studied electrophilic thiocyanatopinacol rearrangement of allyl alcohol and obtained a batch of products with excellent yieldsα-quaternary ammonium salt center-β-thiocyano group a carbonyl compound (a)Org.Lett2019, 21, 9550); in 2021, the professor Chen Fuxue designed and reported the reaction of diaryl-alkynyl substrates with Csp-SCN of N-thiocyanobiphenylsulfonylimide reagent, the reaction substrates were easily available, the yield was excellent, and the atom economy was high (a)J.Org.Chem2021, 86, 5327); in the same year, the team implemented a new strategy involving free radical reaction pathways initiated by AIBN to achieve direct thiocyanide of benzylic compounds, a strategy for constructing benzylic Csp3-SCN bonds: (Chem.Commun.；2021，57，9938）。
Disclosure of Invention
The invention aims to provide a synthetic method of an axial chiral 2-thiocyano-3-aryl-containing indole derivative which has high yield and can be used for preparing a medical intermediate.
The technical scheme adopted by the invention for realizing the purpose is as follows:
an indole derivative or a salt thereof, represented by the formula:
Preferably, the alkyl group is methyl; and/or the aromatic hydrocarbon group is benzyl.
A thiocyano indole derivative or a salt thereof, represented by the formula:
Preferably, the alkyl group is methyl; and/or the aromatic hydrocarbon group is benzyl.
The invention discloses a preparation method of the indole derivative or the salt thereof, which comprises the following steps: adding a substrate containing boric acid groups and an iodo-indole substrate into a solvent, and reacting under the action of a catalytic system to prepare an indole derivative or salt thereof; the iodoindole substrate is 3-iodo-1H-indole-6-carboxylic acid methyl ester; the substrate containing the boric acid group is 2-methoxy-1-naphthalene boric acid, and the catalytic system comprises tetraaminopalladium dichloride.
Preferably, the solvent is a mixed solvent obtained by mixing toluene, ethanol and deionized water.
Preferably, the catalytic system also comprises 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl or N, N ' - (1,2-ethanediyl) ferric (III) bisaspartate disodium salt.
More preferably, tetraaminopalladium dichloride is used in a molar amount of 1-3% of the molar amount of iodoindole substrate; 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl is used in a molar amount of 2-4% of the molar amount of the iodoindole substrate; the molar amount of iron (III) disodium N, N' - (1,2-ethanediyl) bisaspartate used is 1-2% of the molar amount of iodoindole substrate.
The synthetic route given in the present invention is a simplification of the process for the preparation of the indole derivatives of the present invention for the rapid understanding of the synthetic process of the present invention, and is not intended to be a structural limitation of the particular reactants or products, and the need for particular reaction starting materials or intermediates or products depends on the particular materials used. In the above synthetic route of the present invention, either indole derivative a or indole derivative B can be used for the preparation of a thiocyano group-containing indole derivative, indole derivative B is obtained by further treating indole derivative a when a specific group is introduced at a specific position, and indole derivative B is obtained by further treating indole derivative a without further treatment when indole derivative a can be obtained by a further reaction.
Preferably, in the preparation of the indole derivative A, a substrate containing a boric acid group, an iodoindole substrate, a catalytic system and sodium bicarbonate are added into a mixed solvent under a protective gas atmosphere, the mixture is stirred and reacted for 6 to 16 hours at a temperature of between 80 and 120 ℃, after the reaction is finished, a quenching agent is added for quenching, ethyl acetate is used for washing, filtering, concentrating and silica gel flash chromatography is used for purifying to obtain the indole derivative A or salts thereof.
More preferably, in the preparation of the indole derivative a, the protective gas is argon, the mixed solvent is obtained by mixing toluene, ethanol and deionized water, the mixed solvent contains 55-65wt% of toluene, and the mixed solvent contains 15-25wt% of ethanol.
More preferably, in the preparation of indole derivative A, the usage amount of the iodo-indole substrate is 0.3-1.2wt% of the mixed solvent, and the usage molar amount of the substrate containing the boronic acid group is 90-100% of the molar amount of the iodo-indole substrate.
More preferably, in the preparation of indole derivative a, the catalytic system comprises tetraaminopalladium dichloride, which is used in a molar amount of 1-3% of the molar amount of iodoindole substrate.
More preferably, in the preparation of indole derivative A, the catalytic system comprises tetraaminopalladium dichloride and 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl, the tetraaminopalladium dichloride is used in a molar amount of 1-3% of the molar amount of iodoindole substrate, and the 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl is used in a molar amount of 2-4% of the molar amount of iodoindole substrate.
More preferably, in the preparation of indole derivative A, the catalytic system comprises tetraaminopalladium dichloride and iron (III) N, N '- (1,2-ethanediyl) bisaspartate, wherein the molar amount of tetraaminopalladium dichloride used is 1-3% of the molar amount of iodoindole substrate, and the molar amount of iron (III) N, N' - (1,2-ethanediyl) bisaspartate used is 1-2% of the molar amount of iodoindole substrate. The invention can use the catalysis system composed of tetraaminopalladium dichloride and N, N '- (1,2-ethanediyl) ferric (III) bisaspartate, when tetraaminopalladium dichloride is not used, the use of the N, N' - (1,2-ethanediyl) ferric (III) bisaspartate can not catalyze the preparation of indole derivatives, and the formed catalysis system has good preparation effect on indole derivatives only when tetraaminopalladium dichloride exists.
More preferably, in the preparation of indole derivative A, sodium bicarbonate is used in a molar amount of 400-600% of the molar amount of iodoindole substrate.
More preferably, in the preparation of the indole derivative A, the quenching agent is deionized water, and the usage amount of the quenching agent is 10-30wt% of the mixed solvent.
More preferably, in the preparation of indole derivative a, the purification reagents in the purification by silica gel flash chromatography are prepared from PE and EA in a ratio of 20: mixing at a volume ratio of 0.5-2.
Preferably, in the preparation of intermediate 1, indole derivative A is added into DCM under the protective gas atmosphere, stirred and mixed to obtain indole derivative A solution, and BBr is added dropwise 3 And monitoring the reaction process by TLC, adding a quenching agent after the reaction is finished, extracting by ethyl acetate, and purifying by silica gel flash chromatography to obtain an intermediate 1.
More preferably, in the preparation of intermediate 1, the protective gas is argon, and the solution of indole derivative A contains 0.4-1.2wt% of indole derivative A.
More preferably, in the preparation of intermediate 1, BBr 3 The molar amount of the indole derivative A is 250-350 percent of the molar amount of the indole derivative A.
More preferably, in the preparation of intermediate 1, the quenching agent is deionized water, and the amount of the quenching agent is 10-30wt% of the indole derivative A solution.
More preferably, in the preparation of intermediate 1, the purification reagents in the silica gel flash chromatography purification are prepared from PE and EA in a ratio of 8: mixing at a volume ratio of 0.5-2.
Preferably, in the preparation of the indole derivative B, the intermediate 1 is added into dichloromethane under the protective gas atmosphere, stirred and mixed to obtain an intermediate 1 solution, an alkaline reagent is added at the temperature of 0-5 ℃, then a halide is added, the reaction is carried out at room temperature for 8-16h, and after the reaction is finished, silica gel flash chromatography purification is carried out to obtain the indole derivative B or the salt thereof.
More preferably, in the preparation of indole derivative B, the protective gas is argon, and the solution of intermediate 1 contains 0.3-0.9wt% of intermediate 1.
More preferably, in the preparation of indole derivative B, the alkaline agent is sodium hydroxide and the molar amount of the alkaline agent used is 150-250% of the molar amount of intermediate 1.
More preferably, the indole derivative B is prepared using a molar amount of halide that is 120-180% of the molar amount of intermediate 1.
More preferably, in the preparation of indole derivative B, the purification reagents in the purification by silica gel flash chromatography are prepared from PE and EA in a ratio of 100-5:1 by volume.
The invention discloses a preparation method of the indole derivative containing the thiocyano group or the salt thereof, which comprises the following steps: the indole derivative or salt thereof is reacted with N-thiocyano o-benzoylsulfimide in a liquid reagent to prepare the indole derivative or salt thereof containing the thiocyano.
Preferably, in the preparation of the axial chiral sulfur cyano containing indole derivative, the phosphate compound and the phenyl sulfide compound are mixed at room temperature under the atmosphere of protective gas, N-thiocyano-o-benzoylsulfimide is added after the protective gas is replaced, a solvent is added to dissolve the N-thiocyano-o-benzoylsulfimide, the reaction is carried out under stirring, a quenching agent is added after the reaction is finished, and the quenching agent is quenched, and the column chromatography purification is carried out to obtain the sulfur cyano containing indole derivative or the salt thereof.
More preferably, in the preparation of the axial chiral sulfur cyano group-containing indole derivative, the phosphate ester compound is diphenyl phosphate, and the molar amount of the phosphate ester compound is 15 to 25% of the molar amount of the indole derivative.
More preferably, in the preparation of the axial chiral thiocyano-containing indole derivative, the phenyl sulfide compound is 3,3' -dihydroxy diphenyl disulfide, and the molar amount of the phenyl sulfide compound is 15-25% of the molar amount of the indole derivative.
More preferably, in the preparation of the axial chiral thiocyano group-containing indole derivative, N-thiocyano-benzoylsulfonimide is used in a molar amount of 100 to 140% of the molar amount of the indole derivative.
More preferably, in the preparation of the axial chiral thiocyano-containing indole derivative, the solvent is anhydrous dichloromethane, and the amount of the solvent used is 60-300wt% of the indole derivative. The solvent is used for the dissolution reaction of N-thiocyanatophthalimide and the like, and may be used in a desired range according to actual needs, and the content thereof is not particularly limited.
More preferably, in the preparation of the axial chiral thiocyano-containing indole derivative, the quencher is sodium bicarbonate or triethylamine, and the amount of the quencher used is 0.5-2wt% of the solvent.
The invention discloses application of the indole derivative containing the thiocyano group in preparing a medicament.
According to the invention, an indole derivative A or a salt thereof is generated by reacting a substrate containing a boric acid group with an iodoindole substrate under the action of a catalytic system; or, mixing indole derivative A or its salt with BBr 3 After the reaction, the indole derivative B or the salt thereof is generated by the reaction with halide; the catalytic system used in the invention at least comprises tetraaminopalladium dichloride, and also comprises N, N ' - (1,2-ethanediyl) ferric (III) bisaspartate or 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl, and the iodoindole substrate used is 3-iodo-1H-indole-6-carboxylic acid methyl ester, so that the following beneficial effects are achieved: the indole derivative or the salt thereof prepared by the invention has high yield, and can be further prepared into the indole derivative with axial chirality and 2-thiocyano-3-aryl. Therefore, the invention is the axial chirality 2-containing material which has high yield and can be used for preparing the medical intermediateA synthetic method of indole derivatives of thiocyano-3-aryl.
Drawings
FIG. 1 is a graph of yield.
Detailed Description
The technical solution of the present invention is further described in detail below with reference to the following detailed description and the accompanying drawings:
in the following examples, NMR spectra of axial chiral thiocyano-containing indole derivatives ( 1 H NMR、 13 C NMR and 19 f NMR) was determined from Bruker AVANCE III HD, solvent deuterated chloroform, deuterated methanol, deuterated dimethyl sulfoxide, deuterated dichloromethane; chemical shifts (δ) are quoted in ppm, with tetramethylsilane as internal standard, multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet; high Resolution Mass Spectrometry (HRMS) data were obtained by ESI techniques and Q-TOF mass spectrometry using Fourier transform ion cyclotron (SolariX 7.0T).
Example 1:
a preparation method of indole derivative (succinate-1),
preparation of indole derivative (substrate-1): adding a substrate containing a boric acid group, an iodoindole substrate, tetraaminopalladium dichloride and sodium bicarbonate into a mixed solvent under the atmosphere of protective gas, stirring and reacting at the temperature of 100 ℃ for 10 hours, adding a quenching agent after the reaction is finished, quenching, washing with ethyl acetate, filtering, concentrating, and purifying by silica gel flash chromatography to obtain the indole derivative (succinate-1) with the yield of 38%. The protective gas is argon, the mixed solvent is obtained by mixing toluene, ethanol and deionized water, the mixed solvent contains 60wt% of toluene, the mixed solvent contains 20wt% of ethanol, the usage amount of the iodoindole substrate is 0.8wt% of the mixed solvent, the usage molar amount of the substrate containing the boric acid group is 90% of the molar amount of the iodoindole substrate, the usage molar amount of the tetraamino palladium dichloride is 2% of the molar amount of the iodoindole substrate, the usage molar amount of the sodium bicarbonate is 500% of the molar amount of the iodoindole substrate, the quenching agent is deionized water, and the usage amount of the quenching agent is 20wt% of the mixed solvent. Purification reagents in silica gel flash chromatography purification were purified from PE and EA at 20:1 by volume.
The iodoindole substrate is: 3-iodo-1H-indole-6-carboxylic acid methyl ester; the substrate containing the boric acid group is 2-methoxy-1-naphthalene boric acid.
The chemical structural formula of the product is:
。
indole derivatives (substrate-1) were characterized as follows: 1 HNMR（400MHz，Chloroform-d）δ8.77（d，1H），8.21(d，1H)，8.09（d，1H），7.86–7.81（m，1H），7.51–7.45（m，2H），7.41（d，1H），7.33–7.28（m，3H），7.05（ddd，1H），3.85（s，3H），3.82（s，3H）； 13 CNMR（101MHz，CDCl 3 ）155.2，137.9，133.7，130.7，129.3，128.5，128.2，127.4，125.2，124.3，123.1，121.2，121.1，119.8，114.5，113.2，113.2，111.1，109.6，56.4，51.6；HRMS(+ESI)C 20 H 14 N 2 NaOS(M+Na) + the theoretical value of m/z is 331.1208, and the measured value of m/z is 331.1206.
Example 2:
a method for preparing indole derivative (substrate-1),
preparation of indole derivative (substrate-1): adding a substrate containing a boric acid group, an iodoindole substrate, 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl, tetraaminopalladium dichloride and sodium bicarbonate into a mixed solvent under the atmosphere of protective gas, stirring and reacting for 10 hours at the temperature of 100 ℃, adding a quenching agent after the reaction is finished, quenching, washing with ethyl acetate, filtering, concentrating, and purifying by silica gel flash chromatography to obtain an indole derivative (succinate-1), wherein the yield is 42%. The protective gas is argon, the mixed solvent is obtained by mixing toluene, ethanol and deionized water, the mixed solvent contains 60wt% of toluene, the mixed solvent contains 20wt% of ethanol, the using amount of iodoindole substrate is 0.8wt% of the mixed solvent, the using molar amount of substrate containing boric acid group is 90% of the using molar amount of iodoindole substrate, the using molar amount of 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl is 3% of the using molar amount of iodoindole substrate, the using molar amount of tetraaminopalladium dichloride is 2% of the using molar amount of iodoindole substrate, the using molar amount of sodium bicarbonate is 500% of the using molar amount of iodoindole substrate, the quenching agent is deionized water, and the using amount of the quenching agent is 20wt% of the mixed solvent. Purification reagents in silica gel flash chromatography purification were purified from PE and EA at 20:1 by volume.
The iodo indole substrate is: 3-iodo-1H-indole-6-carboxylic acid methyl ester; the substrate containing the boric acid group is 2-methoxy-1-naphthalene boric acid.
Example 3:
a preparation method of indole derivative (succinate-1),
preparation of indole derivative (substrate-1): under the protective gas atmosphere, adding a substrate containing a boric acid group, an iodoindole substrate, N' - (1,2-ethanediyl) ferric (III) bisaspartate, tetraaminopalladium dichloride and sodium bicarbonate into a mixed solvent, stirring and reacting for 10 hours at the temperature of 100 ℃, adding a quenching agent to quench after the reaction is finished, washing with ethyl acetate, filtering, concentrating, and purifying by silica gel flash chromatography to obtain the indole derivative (substrate-1), wherein the yield is 72%. The protective gas is argon, the mixed solvent is obtained by mixing toluene, ethanol and deionized water, the mixed solvent contains 60wt% of toluene, the mixed solvent contains 20wt% of ethanol, the usage amount of the iodoindole substrate is 0.8wt% of the mixed solvent, the usage molar amount of the substrate containing boric acid groups is 90% of the molar amount of the iodoindole substrate, the usage molar amount of N, N' - (1,2-ethanediyl) ferric (III) bisaspartate disodium salt is 2% of the molar amount of the iodoindole substrate, the usage molar amount of tetraaminopalladium dichloride is 2% of the molar amount of the iodoindole substrate, the usage molar amount of sodium bicarbonate is 500% of the molar amount of the iodoindole substrate, the quenching agent is deionized water, and the usage amount of the quenching agent is 20wt% of the mixed solvent. Purification reagents in silica gel flash chromatography purification were purified from PE and EA at a 20:1 by volume.
The iodoindole substrate is: 3-iodo-1H-indole-6-carboxylic acid methyl ester; the substrate containing the boric acid group is 2-methoxy-1-naphthalene boric acid.
Example 4:
a preparation method of indole derivative (substrate-1) is characterized by that 1,1,3,3-tetramethylguanidine can be added in the preparation of indole derivative (substrate-1), and the joint use of 1,1,3,3-tetramethylguanidine, N' - (1,2-ethanediyl) di-ferric aspartate (III) disodium salt and tetra-amino palladium dichloride can further raise the yield of indole derivative (substrate-1), and it has been found that 1,1,3,3-tetramethylguanidine has excellent effect when its used mole quantity is 0.5-1.5% of that of iodo indole substrate.
Preparation of indole derivative (substrate-1): under the protective gas atmosphere, adding a substrate containing a boric acid group, an iodoindole substrate, N' - (1,2-ethanediyl) ferric (III) bisaspartate, 1,1,3,3-tetramethylguanidine, tetraaminopalladium dichloride and sodium bicarbonate into a mixed solvent, stirring and reacting for 10 hours at the temperature of 100 ℃, adding a quenching agent to quench after the reaction is finished, washing with ethyl acetate, filtering, concentrating, and purifying by silica gel flash chromatography to obtain an indole derivative (succinate-1), wherein the yield is 81%. The protective gas is argon, the mixed solvent is obtained by mixing toluene, ethanol and deionized water, the mixed solvent contains 60wt% of toluene, the mixed solvent contains 20wt% of ethanol, the usage amount of iodoindole substrate is 0.8wt% of the mixed solvent, the usage molar amount of substrate containing boric acid group is 90% of the molar amount of iodoindole substrate, N, N' - (1,2-ethanediyl) ferric (III) bisaspartate is 2% of the molar amount of iodoindole substrate, the usage molar amount of 1,1,3,3-tetramethylguanidine is 1% of the molar amount of iodoindole substrate, the usage molar amount of tetraaminopalladium dichloride is 2% of the molar amount of iodoindole substrate, the usage molar amount of sodium bicarbonate is 500% of the molar amount of iodoindole substrate, the quenching agent is deionized water, and the usage amount of quenching agent is 20wt% of the mixed solvent. Purification reagents in silica gel flash chromatography purification were purified from PE and EA at 20:1 by volume.
The iodoindole substrate is: 3-iodo-1H-indole-6-carboxylic acid methyl ester; the substrate containing the boric acid group is 2-methoxy-1-naphthalene boric acid.
Example 5:
a process for the preparation of indole derivative (substrate-2) as used in this example, indole derivative (substrate-1) from example 1.
Preparation of intermediate 1: under the protective gas atmosphere, adding indole derivative (succinate-1) into DCM, stirring and mixing to obtain an indole derivative (succinate-1) solution, and dropwise adding BBr 3 And monitoring the reaction process by TLC, adding a quenching agent after the reaction is finished, extracting by ethyl acetate, and purifying by silica gel flash chromatography to obtain an intermediate 1. The protective gas is argon, and the solution of indole derivative (substrate-1) contains 0.8wt% of indole derivative (substrate-1), BBr 3 The molar amount of the quenching agent is 300 percent of the molar amount of the indole derivative (succinate-1), the quenching agent is deionized water, and the amount of the quenching agent is 20 percent by weight of the solution of the indole derivative (succinate-1). Purification reagents in silica gel flash chromatography purification were purified from PE and EA at 8:1 by volume.
Preparation of indole derivative (substrate-2): adding the intermediate 1 into dichloromethane under the protective gas atmosphere, stirring and mixing to obtain an intermediate 1 solution, adding an alkaline reagent at the temperature of 0 ℃, then adding a halide, reacting at room temperature for 12 hours, and after the reaction is finished, purifying by silica gel flash chromatography to obtain an indole derivative (succinate-2) or a salt thereof with the yield of 48%. The protective gas was argon, the solution of intermediate 1 contained 0.6wt% of intermediate 1, the alkaline reagent was sodium hydroxide, the molar amount of alkaline reagent used was 200% of the molar amount of intermediate 1, the halide was benzyl chloride, and the molar amount of halide used was 150% of the molar amount of intermediate 1. Purification reagents in silica gel flash chromatography purification were purified from PE and EA at 50:1 by volume.
The chemical structural formula of the product is:
。
the indole derivative (substrate-2) was characterized as follows: 1 HNMR（400MHz，Chloroform-d）δ8.72(d，1H)，8.63(d，1H)，7.95(d，1H)，7.86(dd，1H)，7.48(dd，2H)，7.42–7.29(m，4H)，7.21–7.15(m，3H)，7.11–7.05m，3H)，5.21–5.02(m，2H)，3.84（s，3H）； 13 CNMR（101MHz，CDCl 3 ）δ155.1，154.2，137.5，136.7，133.6，130.2，129.5，128.4，128.3，128.2，127.8，127.05，126.2，125.5，124.4，123.6，121.3，120.2，119.5，115.7，115.3，113.2，111.5，109.4，104.2，71.6，51.4；HRMS(+ESI)C 20 H 14 N 2 NaOS(M+Na) + the theoretical value of m/z is 407.1511, and the measured value of m/z is 407.1509.
Example 6:
a method for preparing a thiocyano-containing indole derivative (sulfate-3),
weighing 0.1 mmol of indole derivative (substrate-1), 0.02 mmol of diphenyl phosphate and 0.02 mmol of 3,3' -dihydroxy diphenyl disulfide in a 10 mL reaction tube, replacing argon for three times, moving to a glove box, adding 0.12 mmol of N-thiocyano-o-benzoylsulfimide, rapidly dissolving with anhydrous dichloromethane, stirring at room temperature for 2 hours, adding sodium bicarbonate for quenching, and purifying by column chromatography to obtain a yellow solid, namely the axial chiral thiocyano-containing indole derivative (substrate-3), wherein the yield is 89%.
The chemical structural formula of the axial chiral sulfur cyano group-containing indole derivative is as follows:
。
the axial chiral thiocyano-containing indole derivative (substrate-3) was characterized as follows: 1 HNMR（400MHz，Chloroform-d）δ8.86（s，1H），8.02（d，1H），7.95–7.85（m，1H），7.49–7.46（m，2H），7.45（d， 1H），7.41–7.33（m，3H），7.18（dd，1H），7.09（ddd，1H），3.90(s，3H)，3.82（s，3H）； 13 CNMR（101MHz，CDCl 3 ）δ155.4，138.1，133.9，130.8，129.5，128.7，128.3，127.2，125.1，124.6，123.4，121.6，121.3，120.1，114.2，113.4，113.4，111.2，109.4，56.7，51.8；HRMS(+ESI)C 20 H 14 N 2 NaOS(M+Na) + the theoretical value of m/z is 388.0912, and the measured value of m/z is 388.0908.
Example 7:
a method for preparing a thiocyano-containing indole derivative (sulfate-4),
weighing 0.1 mmol of indole derivative (substrate-2), 0.02 mmol of diphenyl phosphate and 0.02 mmol of 3,3' -dihydroxydiphenyl disulfide in a 10 mL reaction tube, replacing argon for three times, moving to a glove box, adding 0.12 mmol of N-thiocyano-o-benzoylsulfimide, rapidly dissolving with anhydrous dichloromethane, stirring at room temperature for 3 hours, adding sodium bicarbonate for quenching, and purifying by column chromatography to obtain a yellow solid, namely the axial chiral thiocyano-containing indole derivative (substrate-4), wherein the yield is 85%.
The chemical structural formula of the axial chiral sulfur cyano group-containing indole derivative is as follows:
。
the axial chiral thiocyano-containing indole derivative (substrate-4) was characterized as follows: 1 HNMR(400MHz，Chloroform-d)δ8.79(s，1H)，7.94(d，1H)，7.88(dd，1H)，7.53(dd，2H)，7.46–7.33(m，4H)，7.25–7.19(m，3H)，7.14–7.08(m，3H)，5.21–5.01(m，2H)，3.88(s，3H)； 13 CNMR(101MHz，Chloroform-d)δ154.1，153.7，137.2，136.4，133.5，129.9，129.1，128.2，128.1，127.9，127.6，127.08，126.6，125.3，124.2，123.9，121.1，120.7，119.2，115.4，115.1，113.3，111.1，109.2，103.5，71.3，51.2；HRMS(+ESI)C 26 H 18 N 2 NaOS(M+Na) + the theoretical value of m/z is 464.1224, and the measured value of m/z is 464.1222.
Comparative example 1:
a method for preparing indole derivative (substrate-1),
preparation of indole derivative (substrate-1): under the protective gas atmosphere, a substrate containing boric acid groups, an iodoindole substrate, 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl and Pd 2 (dba) 3 Adding sodium bicarbonate into mixed solvent, stirring at 100 deg.C for 10 hr, quenching with quencher, washing with ethyl acetate, filtering, concentrating, and quickly coloring with silica gelAnd (4) carrying out chromatography purification to obtain an indole derivative (substrate-1). The protective gas is argon, the mixed solvent is obtained by mixing toluene, ethanol and deionized water, the mixed solvent contains 60wt% of toluene, the mixed solvent contains 20wt% of ethanol, the using amount of the iodoindole substrate is 0.8wt% of the mixed solvent, the using molar amount of the substrate containing the boric acid group is 90% of the molar amount of the iodoindole substrate, the using molar amount of the 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl is 8% of the molar amount of the iodoindole substrate, and Pd 2 (dba) 3 The using molar weight of the mixed solvent is 2% of the molar weight of the iodo indole substrate, the using molar weight of the sodium bicarbonate is 500% of the molar weight of the iodo indole substrate, the quenching agent is deionized water, and the using amount of the quenching agent is 20wt% of the mixed solvent. Purification reagents in silica gel flash chromatography purification were purified from PE and EA at 20:1, the yield was 29%.
The iodoindole substrate is: 3-iodo-1H-indole-6-carboxylic acid methyl ester; the substrate containing the boric acid group is 2-methoxy-1-naphthalene boric acid.
The yields of the products obtained by the methods of the examples of the present invention are shown in FIG. 1, wherein S1 is the final product obtained by the method of example 1, S2 is the final product obtained by the method of example 2, S3 is the final product obtained by the method of example 3, S4 is the final product obtained by the method of example 4, S5 is the final product obtained by the method of example 5, S6 is the final product obtained by the method of example 6, S7 is the final product obtained by the method of example 7, D1 is the final product obtained by the method of comparative example 1, and a catalyst is required to carry out the reaction in the preparation of indole derivatives, and 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl, pd, which can be used in the prior art 2 (dba) 3 To facilitate the preparation of indole derivatives, but 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl, pd 2 (dba) 3 The system has poor effect in the preparation of indole derivatives (substrate-1), and in order to find a novel catalytic system with good catalytic effect, the invention finds that tetraaminopalladium dichloride can catalyze the formation of indole derivatives (substrate-1), but the effect is weaker than 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl and Pd 2 (dba) 3 The effect of the system (1) is that N, NThe catalyst system comprising the disodium salt of the'- (1,2-ethanediyl) iron (III) bisaspartate and the tetraaminopalladium dichloride has excellent effect, and the use of the catalyst system consisting of the disodium salt of the N, N' - (1,2-ethanediyl) iron (III) bisaspartate and the tetraaminopalladium dichloride is better than that of the catalyst system consisting of 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl, pd 2 (dba) 3 The system of (1) can be used, phosphorus-containing compounds are not used in the system of the ferric N, N ' - (1,2-ethanediyl) bisaspartate (III) disodium salt and the tetraaminopalladium dichloride, the difficulty of waste liquid treatment can be reduced, and when the system of the ferric N, N ' - (1,2-ethanediyl) bisaspartate (III) disodium salt and the tetraaminopalladium dichloride is used, a catalytic system formed by 1,1,3,3-tetramethylguanidine, the N, N ' - (1,2-ethanediyl) bisaspartate (III) disodium salt and the tetraaminopalladium dichloride can be added, so that the yield of the compounds is improved.
The above embodiments are merely illustrative, and not restrictive, and those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, all equivalent technical solutions also belong to the scope of the present invention, and the protection scope of the present invention should be defined by the claims.
Claims (10)
1. An indole derivative or a salt thereof, represented by the formula:
2. An indole derivative or a salt thereof according to claim 1, wherein: the alkyl is methyl; and/or the aromatic hydrocarbon group is benzyl.
3. A thiocyano group-containing indole derivative or a salt thereof represented by the following formula:
4. The thiocyano indole derivative or a salt thereof according to claim 3, which is characterized in that: the alkyl is methyl; and/or the aromatic hydrocarbon group is benzyl.
5. A process for the preparation of an indole derivative or a salt thereof as claimed in any one of claims 1 to 2 which comprises: adding a substrate containing boric acid groups and an iodo-indole substrate into a solvent, and reacting under the action of a catalytic system to prepare an indole derivative or salt thereof; the iodoindole substrate is 3-iodo-1H-indole-6-carboxylic acid methyl ester; the substrate containing the boric acid group is 2-methoxy-1-naphthalene boric acid, and the catalytic system comprises tetraaminopalladium dichloride.
6. The process for producing an indole derivative or a salt thereof according to claim 5, wherein: the solvent is a mixed solvent obtained by mixing toluene, ethanol and deionized water.
7. The process for producing an indole derivative or a salt thereof according to claim 5, wherein: the catalytic system also comprises 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl or N, N ' - (1,2-ethanediyl) bisaspartic acid iron (III) disodium salt.
8. The process for producing an indole derivative or a salt thereof according to claim 7, wherein: the molar amount of the tetraaminopalladium dichloride used is 1-3% of the molar amount of the iodo-indole substrate; 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl is used in a molar amount of 2-4% of the molar amount of the iodoindole substrate; the molar amount of iron (III) disodium N, N' - (1,2-ethanediyl) bisaspartate used is 1-2% of the molar amount of iodoindole substrate.
9. A process for producing a thiocyano group-containing indole derivative or a salt thereof as described in any one of claims 3 to 4, which comprises: a thiocyano group-containing indole derivative or a salt thereof obtained by reacting the indole derivative or a salt thereof according to claim 1 with N-thiocyano-benzoylsulfonimide in a liquid reagent.
10. Use of a thiocyano-containing indole derivative according to any of claims 3 to 4 for the preparation of a medicament.
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